The regulatory functions of NK cells on other immune cells constitute an important link between the innate and the specific immune system. Experiments performed in our laboratory have shown interactions between NK cells and B lymphocytes which result in specific modulations of B cell differentiation. We wish to continue these studies to investigate the mechanism by which NK cells influence B cell differentiation. First, whereas IFN-gamma produced by NK cells can clearly increase the level of the IgG2a response, we postulate that IFN- gamma is an amplification factor for post-switched cells and that NK cells play an additional role in initiating the switch to this isotype that is independent of IFN-gamma but dependent on IL-12. Utilizing IFN- gamma-/- mice, which continues to produce significant amounts of IgG2a, we will investigate the cellular and molecular events that may be involved. In addition, possible interactions of NK cells and accessory cells will be examined in order to determine their effect on the T independent B cell antigen response. These experiments may serve to uncover the switch factor for IgH chain switch to gamma2a and the role of IL-12 in this step. Secondly, we will explore the ability of NK cells to increase the longevity of antibodies induced by T-independent antigens and the mechanism by which this occurs. Finally, the biological significance of the preferential switch to IgG2a induced by NK cells will be investigated by examining the effect of NK cell activation on the growth of a B cell tumor that does not elicit direct NK cytotoxicity.